Studies of the neurobehavioral consequences of concurrent administration of cocaine, marihuana and ethanol in human subjects are proposed. Each of these substances is widely abused alone and recent survey data indicate that the prevalence of polydrug abuse is increasing and now poses a major health problem. Virtually nothing is known about the neurophysiologic or behavioral changes associated with the combined use of these drugs. In addition, the way in which drug interactions influence the reinforcing properties of each compound is not well understood. We propose to conduct parametric evaluations of several doses of each drug alone, and in combination with one other drug. Since the temporal distribution of polydrug abuse is not known, we have selected a pretreatment design in which a second drug will be given once the desired effects of the first drug have been attained. Specifically, the interactions between cocaine and marihuana, between cocaine and ethanol and between marihuana and ethanol will be examined. A multidisciplinary approach will be used to characterize the effects of these drugs on electroencephalographic activity (EEG), auditory evoked potentials (P300), heart rate, respiratory rate, muscle tension, and subjective mood states. In addition, plasma levels of these substances will be measured to determine of individual differences in the effects of concurrent drug administration are due to pharmacokinetic or pharmacodynamic interaction. A second goal is to extend the above studies to determine the effects of marihuana or ethanol pretreatments on subsequent self-administration of cocaine or marihuana. Subjects will gain access to either a marihuana cigarette or a cocaine injection by pushing an operant manipulandum. The P300 evoked potential, a sensitive indicator of brain electrical activity, will be measured just prior to drug self-administration. These data should clarify whether changes in neurophysiologic activity occur antecedent to drug-seeking behavior. Furthermore, data obtained will provide a guide for classifying these drugs on the basis of whether they potentiate, disrupt or have no effect on the reinforcing properties of the other drugs. This information will be particularly useful for predicting and potentially preventing polydrug abuse-related problems.